Inclusion Criteria:
- - Age ≥ 18 years at the time of informed consent.
- - Patient/legal authorized representative (LAR) must be able to provide informed
consent.
- - Patient must have a histologically confirmed diagnosis of locally advanced
unresectable stage III/IV or metastatic stage IV cutaneous or mucosal melanoma that
has progressed on PD-1/PD-L1 therapy:
o For Cohort A, the patient's melanoma must have progressed on prior PD-1
monotherapy.
- - For Cohort B, the patient's melanoma must have progressed on prior combination
PD-1 + LAG-3 blockade.
- - Note: Intervening lines of targeted therapy, chemotherapy, bispecific (e.g.
IMCgp100) and cell-based therapies are permitted between last ICI-based therapy
and the start of study therapy.
- - Note: For cohort A, peptide and mRNA vaccines may have been combined with PD-1
monotherapy as long as no other checkpoint inhibitors were concomitantly
administered.
For cohort B, peptide and mRNA vaccines may have been combined
with combined PD-1 + LAG-3 blockade as long as no other checkpoint inhibitors
were concomitantly administered Note: Prior PD-1 monotherapy (Cohort A) or PD-1
and LAG-3 blockade (Cohort B) may have been given in the neoadjuvant or
adjuvant setting as long as progression is documented within 3 months of the
final dose neoadjuvant/adjuvant therapy.
- - Patients must have measurable disease as defined by RECIST v1.1 o Note: Lesions
previously injected with Talimogene laherparepvec or other local therapies may not
be selected as target lesions unless they have demonstrated subsequent growth after
injection.
- - If a suitable archival tissue sample is available, the patient must be willing to
have this specimen submitted for research.
If an archival sample is not available,
the patient is still a candidate for the trial, and every reasonable effort will be
made to obtain a biopsy if deemed safe.
- - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
° Adequate laboratory function at screening, defined as:
° Hemoglobin ≥ 10 gm/dL (≥ 6.2 mmol/L)
° Platelet count ≥ 100 × 10^9 /L. °Serum direct bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN. (Total bilirubin < 3
mg/dL for subjects with Gilbert's disease)
- - No signs of active coronary ischemia, including ECG changes or elevated troponin if
clinically indicated.
- - Calculated creatinine clearance (CrCl) ≥30 mL/min based on the Cockcroft-Gault
equation.
- - All immune-related adverse events (irAE's) from prior ICI based therapy must have
improved to Grade 1 or lower.
- - All women of childbearing potential (WOCBP)* or sexually active men must practice
highly effective contraception prior to the initial dose/start of the first
treatment, during the study, and for at least 6 months after the last dose.
Highly
effective contraceptive measures in women include. o Stable use of combined (estrogen and progestogen containing) hormonal
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal
contraception (oral, injectable, implantable) associated with inhibition of
ovulation initiated 2 or more menstrual cycles prior to screening,
- - Intrauterine device (IUD),
- Intrauterine hormone-releasing system (IUS),
- Bilateral tubal ligation,
- Vasectomized partner,† and/or.
‡,§
- - Male study participants with WOCBP partners are required to use condoms unless they
are vasectomized† or practice sexual abstinence.
‡,§
- - * WOCBP are defined as women who are fertile following menarche until becoming
postmenopausal, unless permanently sterile.
A postmenopausal state is defined as no
menses for 12 months without an alternative medical cause. A high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a
postmenopausal state in women not using hormonal contraception or hormonal
replacement therapy. However, in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient to determine the occurrence of a postmenopausal
state. The above definitions are according to Clinical Trial Facilitation Group
(CTFG) guidance. Pregnancy testing and contraception are not required for women with
documented hysterectomy or tubal ligation. Permanent sterilization methods include
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
- - Vasectomized partner or vasectomized study participant must have received
medical assessment of the surgical success.
- - Sexual abstinence is considered a highly effective method only if defined
as refraining from heterosexual intercourse during the entire period of
risk associated with the study drugs.
The reliability of sexual abstinence
needs to be evaluated in relation to the duration of the clinical trial
and the preferred and usual lifestyle of the patient.
- - Periodic abstinence (calendar, symptothermal, post-ovulation
methods), withdrawal (coitus interruptus), spermicides only, and
lactational amenorrhea method (LAM) are not acceptable methods of
contraception.
Female condom and male condom should not be used
together.
Exclusion Criteria:
- - Untreated central nervous system (CNS) metastases or leptomeningeal involvement;
patients with brain metastases definitively treated with surgery or stereotactic
radiosurgery (SRS) are permitted.
- - Receipt of the following prior therapies:
- For Cohort A: Any prior anti-LAG-3 (e.g., relatlimab) or CTLA-4 (e.g.,
ipilimumab) directed therapy, unless it was given in the adjuvant or
neoadjuvant setting and the last dose was given more than three months prior to
disease recurrence.
- - For Cohort B: Any prior CTLA-directed therapy (e.g., ipilimumab), unless it was
given in the adjuvant or neoadjuvant setting and the last dose was given more
than three months prior to disease recurrence.
- - Prior Grade 3 or greater neurologic toxicity associated with a prior line of ICI
therapy.
- - Any prior myocarditis associated with ICI therapy.
- - Concurrent systemic steroid therapy higher than physiologic dose steroid replacement
(>7.5 mg/day of prednisone or equivalent), given within 14 days of starting
treatment, or other immunosuppressive medications within 14 days of the start of
treatment.
Inhaled or topical steroids are permitted in the absence of active
autoimmune disease.
- - Receipt of a live vaccine within 30 days of planned start of study medication.
- - Significant infection requiring systemic antibiotics within 2 weeks of the planned
start of study medication (e.g., pneumonia, cellulitis)
- Uncontrolled (i.e., unstable) concomitant medical condition or organ system
dysfunction which, in the treating Investigator's opinion, could compromise the
patient's safety or compliance with the study procedures.
- - Other active, concurrent malignancy that requires ongoing systemic treatment or
interferes with radiographic assessment of melanoma response as determined by the
treating investigator.
- - History of severe hypersensitivity reactions to any unknown allergens or any
components of the study drugs (active ingredients or excipients)
- Has uncontrolled infection with human immunodeficiency virus, hepatitis B, or
hepatitis C infection; or has a diagnosis of immunodeficiency.
Notes:
- - Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV)
at screening.
- - Patients with known HIV infection who have controlled infection (undetectable
viral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a
stable antiviral regimen) are permitted.
For patients with controlled HIV
infection, monitoring will be performed per local standards.
- - Patients with hepatitis B (HBsAg+) who have controlled infection (serum
hepatitis B virus DNA PCR that is below the limit of detection and receiving
anti-viral therapy for hepatitis B) are permitted.
Patients with controlled
infections must undergo periodic monitoring of HBV DNA. Patients must remain on
anti-viral therapy for at least 6 months beyond the last dose of
investigational study drug.
- - Patients who are hepatitis C virus antibody positive (HCV Ab+) who have
controlled infection (undetectable HCV RNA by PCR either spontaneously or in
response to a successful prior course of anti-HCV therapy) may be enrolled into
the study.
- - Patients who are breastfeeding or who are pregnant as evidenced by a positive serum
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performed
within 14 days of the first dose of study drug.
- - Prisoners or participants who are involuntarily incarcerated.
(Note: Under certain
specific circumstances where local regulations permit, a person who has been
imprisoned may be permitted to continue as a participant.)
- Participants who are compulsorily detained for treatment of either a psychiatric or
physical illness (e.g., transmissible infection)
